Minimal residual disease in multiple myeloma: why, when, where

Improvements in multiple myeloma therapy have led to deeper responses that are beyond the limit of detection by historical immunohistochemistry and conventional flow cytometry in bone marrow samples. In parallel, more sensitive techniques for assessing minimal residual disease (MRD) through next-generation flow cytometry and sequencing have been developed and are now routinely available. Deep responses when measured by these assays correspond with improved outcomes and survival. We review the data supporting MRD testing as well as its limitations and how it may fit in with current and future clinical practice.

Upfront therapy: the case for continuous treatment

Both BTKi and BCL2i are regarded as standards of care for frontline treatment of CLL. In this paper, I present the arguments for favoring BTKi as initial therapy. Venetoclax-based regimens have the advantage of being fixed in duration, but patients with select high-risk features may experience inferior PFS relative to those without high-risk features.

Unexplained arterial thrombosis: approach to diagnosis and treatment

Arterial thrombotic events in younger patients without a readily apparent etiology present significant diagnostic and management challenges. We present a structured approach to diagnosis with consideration of common causes, including atherosclerosis and embolism, as well as uncommon causes, including medications and substances, vascular and anatomic abnormalities, systemic disorders, and thrombophilias. We highlight areas of management that have evolved within the past 5 years, including the use of dual-pathway inhibition in atherosclerotic disease, antithrombotic therapy selection in embolic stroke of undetermined source and left ventricular thrombus, the role of closure of patent foramen ovale for secondary stroke prevention, and the thrombotic potential of coronavirus disease 2019 infection and vaccination. We conclude with a representative case to illustrate the application of the diagnostic framework and discuss the importance of consideration of bleeding risk and patient preference in determining the appropriate management plan.

Management of hemolytic transfusion reactions

Delayed hemolytic transfusion reactions (DHTRs) in patients with sickle cell disease are underappreciated and potentially fatal. Patients with DHTRs typically have symptoms of pain or dark urine days to weeks following a red blood cell (RBC) transfusion. In instances of DHTRs with hyperhemolysis, the patient's hemoglobin (Hgb) may be significantly lower than it was pretransfusion, and the Hgb A may drop by more than 50%. In most cases, at least 1 RBC alloantibody and sometimes multiple RBC alloantibodies can be identified during the DHTR, with those antibodies presumably having fallen below the level of detection at the time of the implicated transfusion. However, in up to one-third of cases, no new RBC alloantibodies can be identified posttransfusion. Complement is increasingly being appreciated to play a role in DHTRs and hyperhemolysis, not only due to classic pathway activation (with complement fixed antibody bound to RBCs) but also due to alternative pathway activation (resulting in part from plasma free heme). As such, anti-C5 inhibition has recently been reported to be effective at mitigating hemolysis in the setting of some severe DHTRs. Transfusion avoidance during DHTRs is recommended if possible, with long-term transfusion support advice being less clear; for example, a history of a severe DHTR may lead to questions regarding the safety of transfusions prior to curative therapies such as stem cell transplantation or gene therapy. A better understanding of antibody-positive and antibody-negative DHTRs, including patient- or disease-specific risk factors, is necessary to improve transfusion safety.

Evidence-Based Minireview: In young children with severe sickle cell disease, do the benefits of HLA-identical sibling donor HCT outweigh the risks?

In case 1, a 14-month-old male child with sickle cell disease (SCD) was referred for evaluation for an allogeneic hematopoietic stem cell transplant (HCT). The patient had a history of dactylitis 3 times in his first year of life and febrile episodes twice at the consult. His 4-year-old sister was found to be human leukocyte antigen (HLA) identical. The patient was started on hydroxyurea (HU) at 2.5 years of age. His parents again sought consultation when he was 5 years old because of concerns about his medical condition. At the time, the patient had experienced 2 vaso-occlusive pain episodes (VOEs) requiring hospitalization during the previous 2 years. He had also experienced intermittent pain crises requiring rest at home for 2 to 3 days. The child has not attended school in person due to the COVID-19 pandemic. The family is considering HCT but is ambivalent about it because of potential toxicity. In case 2, an 8-year-old female child is 3 years out from HCT for SCD from her HLA-identical sibling. Before HCT, despite receiving HU, she had experienced >5 VOEs requiring hospitalization and 2 episodes of acute chest syndromes in the previous 3 years. She had also been missing almost 50 days of school days each year. After HCT, she is now attending school regularly and participating in all normal age-appropriate activities. The parents believe that HCT has been transformative in their child's life.

Lower risk but high risk

Risk stratification is crucial to the appropriate management of most cancers, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary from a few months to more than a decade, accurate disease prognostication is especially important. Currently, patients with MDS are often grouped into higher-risk (HR) vs lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations. Factors such as molecular genetic information or disease characteristics not captured in the International Prognostic Scoring System–Revised (IPSS-R) can alter risk stratification and identify a subset of patients with LR-MDS who actually behave more like those with HR-MDS. This review describes the current identification and management of patients with LR-MDS whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R.

How to manage bleeding disorders in aging patients needing surgery

With improvements in medical care, the life expectancy of patients with bleeding disorders is approaching that of the general population. A growing population of older adult patients with bleeding disorders is at risk of age-related comorbidities and in need of various elective and emergent age-related procedures. The increased risk of thrombosis and volume overload in older adults complicates perioperative hemostatic management. Furthermore, antithrombotic treatment such as antiplatelet or anticoagulant therapy, which is frequently required for various cardiovascular interventions, requires a meticulous individualized approach. Evidence-based guidelines for the management of aging patients with bleeding disorders are lacking, largely due to the underrepresentation of older adult patients in clinical trials as well as the rarity of many such bleeding disorders. We discuss the current guidelines and recommendations in the perioperative hemostatic management of older adult patients with hemophilia and von Willebrand disease as well as other rare bleeding disorders. The optimal management of these patients is often complex and requires a thorough multidisciplinary and individualized approach involving hematologists, surgeons, anesthesiologists, and the specialists treating the underlying disorder.

Acute GVHD: think before you treat

The treatment of acute graft-versus-host disease (aGVHD) has become more nuanced in recent years with the development of improved risk classification systems and a better understanding of its complex, multisystem pathophysiology. We review contemporary approaches to the risk stratification and initial treatment of aGVHD, including ongoing clinical trials. We summarize the findings that led to the first US Food and Drug Administration approval for steroid-refractory aGVHD (SR-aGVHD), ruxolitinib, as well as some of the challenges clinicians still face in treating SR-aGVHD. Finally, we discuss the evaluation and management of steroid-dependent aGVHD, which affects approximately one-third of patients who have long-term, waxing and waning symptoms distinct from chronic GVHD. Future clinical trials for aGVHD treatment may identify steroid-sparing approaches for patients who have a high likelihood of response and approaches to improve tissue repair and dysbiosis for those unlikely to respond to immunosuppression alone.

Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies

The adage for smoldering myeloma (SMM) has been to observe without treatment, until criteria for active multiple myeloma were satisfied. Definitions and risk stratification models have become more sophisticated, with prognostication tailored to include high-risk cytogenetics as per the most recent International Myeloma Working Group 2020 risk model. Moreover, progress in defining genomic evolution and changes in the bone marrow microenvironment through the monoclonal continuum have given insight into the complexities underlying the different patterns of progression observed in SMM. Given recent data showing improved progression-free survival with early intervention in high-risk SMM, the current dilemma is focused on how these patients should be treated. This case-based article maps the significant advancements made in the diagnosis and risk stratification of SMM. Data from landmark clinical trials will also be discussed, and ongoing trials are summarized. Ultimately, we outline our approach to SMM and hope to impart to the reader a sound concept of the current clinical management of SMM.

Perioperative consultative hematology: can you clear my patient for a procedure?

Periprocedural management of antithrombotics is a common but challenging clinical scenario that renders patients vulnerable to potential adverse events such as bleeding and thrombosis. Over the past decade, periprocedural antithrombotic approaches have changed considerably with the advent of direct oral anticoagulants (DOACs), as well as a paradigm shift away from bridging in many warfarin patients. Successfully navigating this high-risk period relies on a number of individualized patient assessments conducted within a framework of standardized, systematic approaches. It also requires a thorough understanding of antithrombotic pharmacokinetics, multidisciplinary coordination of care, and comprehensive patient education and empowerment. In this article, we provide clinicians with a practical, stepwise approach to periprocedural management of antithrombotic agents through case-based examples of relevant clinical scenarios.